The present invention relates to an improved method of producing zero-order controlled-release devices.
Zero-order controlled-release devices are well known and have many uses. For example, Cowsar et al. (D. R. Cowsar, O. R. Tarwater, and A. C. Tanquary,) in their article "Controlled Release of Fluoride from Hydrogels for Dental Applications", in ACS Symposium Series, No. 31, Hydroqels for Medical and Related Applications, Joseph D. Andrade, Ed., American Chemical Society, Washington, D.C., p. 180, (1976) describes an intraoral fluoride-releasing device suitable for delivering sodium fluoride in the mouth continuously for six months. The device comprised a core of sodium fluoride entrapped in a 50:50 hydroxyethyl methacrylate (HEMA):methyl methacrylate (MMA) copolymer and a Fick's Law membrane coating of 30:70 HEMA:MMA. Devices were prepared singularly in two steps by (1) adding 60:40 acetone: p-dioxane to a mixture of 60 to 80 wt% sodium fluoride and 40 to 20% 50:50 HEMA:MMA to make a thick paste which was cast in precision cavity molds and dried, and (2) dipping the fluoride-containing cores repeatedly into a 12 wt% solution of 30:70 HEMA:MMA in 60:40 acetone:p-dioxane and allowing the solvent to evaporate between each dipping to form a Fick's Law membrane encasing the cores.
Moreover, Cowsar et al. have shown that these devices are extremely promising in preventing dental caries in man (D. R. Cowsar, T. R. Tice, and D. B. Mirth, "An Intraoral Fluoride-Releasing Device for Prevention of Dental Caries", in Proceedings of the 12th International Symposium on Controlled Release of Bioactive Materials, N. A. Peppas and R. J. Haluska, Eds, Geneva, Switzerland, p. 310, 1985).
The intraoral fluoride-releasing devices described above are just one classic reservoir-type devices having zero-order (constant) release kinetics. Such devices obey Fick's Law of Diffusion because the rate of release of agent, such as fluoride, from the device varies directly with the surface area of the device and inversely with the thickness of the rate-controlling membrane. Because these devices typically deliver drugs, both the rate and the duration of release must be controlled precisely for maximum therapeutic effect with a minimum of toxicity.
Unfortunately, the full potential for this technology has not been met. The laboratory manufacturing process used to produce these devices is laborious and time consuming. For example, for each device produced by the above-described process, approximately 20 minutes was required between each dipping and approximately 14 dippings were required to produce a rate-controlling membrane of about 0.01 cm in thickness. Although that laboratory dipping process could be "scaled-up" to produce numerous devices simultaneously, the manufacturing in commercial quantities requires producing 10,000 or more devices in one batch operation. Also, the current method results in a large amount of residual p-dioxane.
Furthermore, the current method of applying the core around the agent is also problematic. According to the traditional method of coating in a fluidized-bed process, the cores are suspended in an upward-flowing column of hot air, and a solution of the coating polymer is sprayed continuously onto the fluidized bed of tumbling cores. As solvent/polymer microdroplets strike the surface of the cores, the droplets spread on the surface until the solvent evaporates, thereby leaving a "piece" of polymer coating deposited on the core. The process is continued until the cores become fully coated, and then it is continued further until the coating thickness builds to the desired level.
Because the coating has to function as a rate-controlling membrane that obeys Fick's Law of Diffusion, it requires homogeneous, continuous coatings without either gross or micro defects. However, the currently used single solvent process does not provide Fickian membranes. In the current fluidized-bed processes, the solvent for the coating polymer must evaporate fast enough so that the surfaces of the cores never become sticky. If they become sticky, twinning (two fused cores) or gross agglomeration occurs. On the other hand, if the solvent evaporates too quickly, the polymer coating is deposited as discrete heterogeneous particles or flakes. Heterogeneous coatings do not obey Fick's Law of diffusion because the drug is released at a fast rate through discontinuities in the coating.
Therefore, there exists a need for an improved method of producing zero-order, controlled-released devices.
There also exists a need for a cost efficient method of producing such devices on a large-scale basis.
There exists a further need for an improved method of producing a device which releases fluoride at a zero-order controlled rate over a long period of time.